There are many psychotic states for which therapeutic treatments are under investigation. Drugs which are currently available on the market are thought to act as antagonists at the dopaminergic receptors located in the Central Nervous System (CNS), examples of such drugs being haloperidol and chlorpromazine. These drugs typically induce long lasting and sometimes irreversible side-effects, such as tardive dyskinesia. Thus, the search for improvements in therapy for psychotic disorders has been directed to use of drugs with a different mode of action.
Phencyclidine [1-(-phenylcyclohexyl)piperidine; PCP] is a known general anesthetic and is in use as an animal tranquilizer. PCP is a potent psychotomimetic agent used frequently as a "street" drug. Widespread abuse of PCP has led to increased incidence of PCP-induced psychoses [C. V. Showalter et al, Amer. J Psychiat., 134, 1234 (1977)]. PCP abusers experience an apparent sensory isolation accompanied by a feeling of depersonalization which can be terrifying to the person. These subjective changes make PCP an appropriate drug model for study of schizophrenia. The most impressive evidence that PCP psychosis resembles schizophrenia is the fact that drug users have been mistaken by experienced psychiatrists for schizophrenics before obtaining the history of drug use [S. H. Snyder, Nature, 285, 355-356 (1980)].
PCP has been reported to modulate allosterically the NMDA receptor [P. Loo et al, Eur. J. Pharmacol., 123, 467-468 (1986)] and it has been speculated that the psychotomimetic activity of PCP is related to its antagonism of NMDA transmission [C. A. Tamminga et al, Synapse, 1, 497-504 (1987)]. Facilitation of NMDA transmission by action at the glycine modulatory site may antagonize the effect of an endogenous PCP-like ligand [R. Quirion et al, Peptides, 5, 967-973 (1984)].
Amino-oxazolidone compounds have been investigated for CNS effects. For example, the compound D-cycloserine, in its D- and L-isomer forms, has been evaluated for CNS effects in animals [O. Mayer et al, Arzneim. Forsch., 21(2), 298-303 (1971)]. These cycloserine isomers have also been evaluated for psychological and physiological effects in human subjects. For example, D-cycloserine when administered at 500 mg/day doses to healthy human subjects, appeared to stimulate slight sociability, but with depressed mental alertness [M. Vojtechovsky, Act. Nerv. Super., 7(3), 269 (1965)]. Also, D-cyloserine has been administered at 1000 to 1500 mg/day to healthy volunteers whose blood levels showed increased levels of monoamine oxidase enzyme activity [V. Vitek et al, Psychopharmacologia, 7(3), 203-219 (1965)].
D-cycloserine has been investigated as a therapeutic agent for mental disorders in clinical trials, wherein D-cycloserine was administered to mentally disturbed patients at doses of 500 mg. per day [G. E. Crane, Compr. Psychiat., 2, 51-53 (1961)]. In such clinical trials, improvements in depression, insomnia, anexoria or tension were found for some patients, while patients suffering from severe neurosis or psychosis responded poorly to such medication. Moreover, D-cycloserine has been used to exacerbate the symptoms of schizophrenia in an attempt to cure the ailment by symptom provocation [J. Simeon et al, Compr. Psychiat., 11, 80-88, (1970)].
It appears that D-cycloserine, at the dose levels used in these studies, is acting as an antagonist at the glycine site of the NMDA-PCP receptor complex mimicking the action of PCP by inducing psychosis.